tbuckley/cabot-search huggingface dataset:
Effect of silencing tumoral carbohydrate sulfotransferase 15 on T cells in a murine model of pancreatic cancer.
Authors: Juanjuan Ye, Futoshi Suizu, Keiko Yamakawa, Motohiko Kato, Takayoshi Tsuchiya, Hiroyuki Yoneyama, Naohisa Yahagi, Yoko Matsuda
Journal: Journal of Clinical Oncology (2022)

e16241 Background: Limited T cell infiltration within immunosuppressive microenvironment is still a hurdle for immune checkpoint inhibition therapies in pancreatic cancer. Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan biosynthetic enzyme and responsible for tumor matrix remodeling. To investigate the role of CHST15 on tumor immune microenvironment, we evaluated the changes in tumor immune cell profiling in a syngeneic mouse model by implanting pancreatic cancer cells with silencing of CHST15 gene. Methods: We constructed CHST15 shRNA-transfected mouse pancreatic cancer cell line KPC, confirmed repression of CHST15 protein then used as tumor-specific CHST15 knocked-down KPC (CHST15 KD). Wild-type KPC (WT) or CHST15 KD cells were implanted subcutaneously to left hind footpad of syngeneic C57BL/6J mice and the tumor growth was monitored. Kinetics of immune cell components were analyzed by immunohistochemical staining for both tumor microenvironment and tumor draining lymph node (TDLN) at weeks 1, 2, 3 and 4 after inoculation (n = 5-6 at each time point). Results: In the WT group, tumor growth was accelerated from week 2 to week 4, while the growth was almost completely inhibited in the CHST15 KD group. Quantitative analyses for immune-stained tissues at week 4 showed the significant repression of CHST15 in the CHST15 KD group. This was associated with the significant increase of CD3 + , CD4 + and CD8 + T cells in tumor microenvironment, while T cells were barely detected in the WT group. A significant number of EdU + proliferating T cells and Granzyme + CD8 + T cells were found in the CHST15 KD group compared to the WT group. In the TDLN, EdU + CD4 + and CD8 + T cells were diminished at week 2 from week 1 in the WT group, suggesting active T cell suppression occurred at week 2, which was prior to rapid tumor expansion. In strikingly contrast, massive proliferation of CD4 + and CD8 + T cells was observed in the CHST15 KD group from week 2. RNA expression analysis revealed that anti-tumor T cell activity-related genes including recognition of cancer cells by T cells, cancer antigen presentation, killing of cancer cells, were significantly up-regulated in both tumor and TDLN in the CHST15 KD group. These results suggest that tumoral CHST15 remotely provides T cell suppressive signal to TDLN and blockade of CHST15 reactivates T cell immunity, leading to accelerated tumor-infiltrating T cells. Conclusions: The present study demonstrated that blockade of tumoral CHST15 augments the number of activated tumor-infiltrating T cells and inhibits tumor growth in mouse pancreatic cancer. The effect of tumoral T cell accumulation is followed by boosted T cell priming in immune suppressive TDLN. These findings suggest the possibility of a new immunotherapy by enhancing T cell infiltration in refractory pancreatic cancer.
A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA–MONO/GOG-3020/ENGOT-ov45)
Authors: Bradley J. Monk, Christine Parkinson, Myong Cheol Lim, David M. O'Malley, Ana Oaknin, Michelle K. Wilson, Robert L. Coleman, Domenica Lorusso, Paul Bessette, Sharad Ghamande, Athina Christopoulou, Diane Provencher, Emily Prendergast, Fuat Demirkiran, Olga Mikheeva, Oladapo Yeku, Anita Chudecka-Glaz, Michael Schenker, Ramey D. Littell, Tamar Safra, Hung-Hsueh Chou, Mark A. Morgan, Vít Drochýtek, Joyce N. Barlin, Toon Van Gorp, Fred Ueland, Gabriel Lindahl, Charles Anderson, Dearbhaile C. Collins, Kathleen Moore, Frederik Marme, Shannon N. Westin, Iain A. McNeish, Danny Shih, Kevin K. Lin, Sandra Goble, Stephanie Hume, Keiichi Fujiwara, Rebecca S. Kristeleit
Journal: Journal of Clinical Oncology (2022)

ATHENA (ClinicalTrials.gov identifier: NCT03522246) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA-MONO comparison of rucaparib versus placebo. Patients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and timing of surgery. The primary end point of investigator-assessed progression-free survival was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/loss of heterozygosity high tumor), and then in the intent-to-treat population. As of March 23, 2022 (data cutoff), 427 and 111 patients were randomly assigned to rucaparib or placebo, respectively (HRD population: 185 v 49). Median progression-free survival (95% CI) was 28.7 months (23.0 to not reached) with rucaparib versus 11.3 months (9.1 to 22.1) with placebo in the HRD population (log-rank P = .0004; hazard ratio [HR], 0.47; 95% CI, 0.31 to 0.72); 20.2 months (15.2 to 24.7) versus 9.2 months (8.3 to 12.2) in the intent-to-treat population (log-rank P < .0001; HR, 0.52; 95% CI, 0.40 to 0.68); and 12.1 months (11.1 to 17.7) versus 9.1 months (4.0 to 12.2) in the HRD-negative population (HR, 0.65; 95% CI, 0.45 to 0.95). The most common grade ≥ 3 treatment-emergent adverse events were anemia (rucaparib, 28.7% v placebo, 0%) and neutropenia (14.6% v 0.9%). Rucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ovarian cancer with and without HRD.
APAC treatment limits collar-induced carotid atherosclerotic plaque development in apoE-/- mice
Authors: I Bot, L Delfos, E Hemme, PT Kovanen, A Jouppila, R Lassila
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation Introduction and aim: Mimics of mast cell-derived heparin proteoglycans (HEP-PG) can be tailored to molecules carrying both antiplatelet and anticoagulant properties. These dual antiplatelet and anticoagulant (APAC) constructs can also shield adhesion molecules such as P-selectin and VCAM-1 expressed by endothelial cells upon atherosclerosis development. We hypothesize that via this way, APAC prevents macrophage accumulation and lesion development. In this study, we therefore determined the efficacy of APAC in inhibiting atherosclerosis. Methods Male western-type diet fed apoE-/- mice were equipped with perivascular carotid artery collars to induce atherosclerosis. In this collar model, mRNA expression of adhesion molecules such as ICAM-1, VCAM-1, P-Selectin but also of Platelet Factor 4 (PF4) are significantly upregulated upon lesion development (all P&amp;lt;0.05 at 2 weeks after collar placement compared with control arteries). From lesion initiation, mice were treated with 0.2 mg/kg APAC or vehicle control (i.v, 3x per week, n=12-14 per group) for 2.5 weeks. At 5 weeks after collar placement, mice were sacrificed. Results APAC treatment did not affect body weight or plasma total cholesterol levels of the mice during the experiment. Interestingly, carotid artery plaque size was reduced by over 50% upon APAC treatment (APAC: 50±10*10E3 versus controls: 102±13*10E3 square µm; P&amp;lt;0.01). This observation was aligned with reduced plaque macrophage area (APAC: 20±5*10E3 versus controls: 33±5*10E3 square µm) and collagen content (APAC: 13±4*10E3 versus controls: 28±6*10E3 square µm; P&amp;lt;0.05). Conclusion We here show that APAC effectively inhibits atherosclerotic lesion development when administered during lesion initiation and may have potential as therapeutic agent to prevent atherosclerosis.
Antibody responses to BNT162b2 mRNA COVID-19 vaccine in healthcare workers and patients with urological diseases in Japan
Authors: S. Hatakeyama, T. Yoneyama, T. Hamaya, K. Togashi, T. Narita, N. Fujita, H. Yamamoto, T. Yoneyama, Y. Hashimoto, C. Ohyama
Journal: European Urology (2022)
Intrauterine device-related uterine perforation incidence and risk (APEX-IUD): a large multisite cohort study
Authors: Susan D Reed, Xiaolei Zhou, Laura Ichikawa, Jennifer L Gatz, Jeffrey F Peipert, Mary Anne Armstrong, Tina Raine-Bennett, Darios Getahun, Michael J Fassett, Debbie A Postlethwaite, Jiaxiao M Shi, Alex Asiimwe, Federica Pisa, Juliane Schoendorf, Catherine W Saltus, Mary S Anthony, Susan D. Reed, Xiaolei Zhou, Laura Ichikawa, Jennifer L. Gatz, Jeffrey F. Peipert, Mary Anne Armstrong, Tina Raine-Bennett, Darios Getahun, Michael J. Fassett, Debbie A. Postlethwaite, Maqdooda Merchant, Amy L. Alabaster, Giulia Chillemi, Jiaxiao M. Shi, Fagen Xie, Vicki Y. Chiu, Theresa M. Im, Harpreet S. Takhar, Alex Asiimwe, Federica Pisa, Juliane Schoendorf, Mary E. Ritchey, Kenneth J. Rothman, Catherine W. Saltus, Shannon Hunter, Jinyi Wang, Mary S. Anthony
Journal: The Lancet (2022)
Utilization and financial coverage of blood based next generation sequencing for solid tumors: A study from Augusta-Georgia.
Authors: Erica Lampkin, Nabin Raj Karki, Sabrina Matosz, Mycal Casey, Christian Leurinda, Nagla Fawzy Abdel Karim
Journal: Journal of Clinical Oncology (2022)

e18592 Background: There is an increasing trend of integrating molecular profiling to devise treatment plans for solid malignancies. Tumor testing for specific clonal abnormalities is being supplanted by broad multigene panel testing from blood specimen, aptly labelled liquid biopsy. Due to varying utility across malignancies in differing contexts and issues of access and affordability, their adoption is not uniform. We attempt to characterize the pattern of utilization across tumor types and financial coverage schemes in an academic cancer institute in southeastern United States. Methods: All blood based next generation testing samples ordered by providers affiliated to Georgia Cancer center between January 1, 2017, and December 31, 2021, via Guardant platform for all solid tumors was included in this analysis. Guardant360 and Guardant360CDx assays tested for upto 83 cancer related genes in circulating cell-free DNA in patients of solid tumors. Primary cancer diagnosis, insurance information and turnaround time was obtained from Guardant. Results: 296 tests were sent from January 1, 2017, through December 31, 2021. The total number of tests performed in year 2017, 2018, 2019, 2020 and 2021 were 1, 3, 28, 99 and 165 respectively. Billing information was available for all cases, clinical information was available for 262 cases. Average turnaround time was 8.5 days overall. 221 Guardant360 was sent with average turnaround time of 10 days. 41 Guardant360CDx was sent with average turnaround time of 7 days. The frequency of malignancies in the order of dimensioning frequency were lung 50.7%, prostate 12.1%, breast 6.9%, kidney 3.8% and colorectal 3.4%. The remaining 22.1% comprised of pancreatic, melanoma, glioblastoma, and bladder malignancies. The test was covered by private insurance/employee health plan in 53.4% (158/296), Medicare in 31.1% (92/296) and Medicaid in 10.5% (31/296) (table). 4.7% (14/296) qualified for free of charge testing (financial indigent) and 0.3% (1/296) were self-pay (table). Conclusions: There is an increase in the utilization of liquid biopsy to perform comprehensive genomic analysis. The distribution of tumor types is not entirely explained by the incidence and availability of targeted therapies for each type. Private insurers accounted for most of the tests being done. The disparities in utilization of this platform across different tumor types and payment models deserve further exploration. T[Table: see text]
The analgesic compound palmitoylethanolamide reduces inflammation in human cardiomyocytes and vascular endothelial cells exposed to doxorubicin and anti-HER2 monoclonal antibody through PPAR-α and NLRP3-related pathways.
Authors: Martina Iovine, Vincenzo Quagliariello, Simona Buccolo, Andrea Paccone, Michelino De Laurentiis, Nicola Maurea
Journal: Journal of Clinical Oncology (2022)

e24054 Background: Palmitoylethanolamide (PEA) is an endogenous fatty acid mediator that is synthetized from membrane phospholipids by N-acyl phosphatidylethanolamine phospholipase D. It is a new analgesic drug with anti-inflammatory effects through the induction of PPAR-related pathways. We aimed to assess whether palmitoylethanolamide co-incubated during doxorubicin and trastuzumab, reduces anticancer drugs-related cardiotoxicity in cellular models. Methods: Human vascular endothelial cells and cardiomyocytes were exposed to subclinical concentration of doxorubicin (at 100 and 200 nM) combined to trastuzumab (at 100 and 200 nM) alone or in combination with a formulation composed by palmitoylethanolamide 500 nM for 48h. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of peroxisome proliferator-activated receptor-α; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). Results: Palmitoylethanolamide co-incubated with doxorubicin exerts vasculoprotective and cardioprotective effects, enhancing cell viability of 56.3-78.7 % compared to untreated cells (p &lt; 0,001 for all). Notably, PEA reduced significantly the cardiotoxicity through peroxisome proliferator-activated receptor-α –related pathways and NLRP3 inflammasome but without the involvement of calcium homeostasis. Several cytokines and chemokines were also reduced confirming its anti-inflammatory effect. Conclusions: The present study demonstrates that palmitoylethanolamide protects against vasculotoxicity and cardiotoxicity of doxorubicin and trastuzumab by promoting an anti-inflammatory phenotype, representing a new therapeutic approach to resolve doxorubicin-induced vasculo-cardio toxicity and inflammation.
Transrectal ultrasound guided hydro dissection of the rectum-vesicular layer before robot assisted radical prostatectomy: Proposal of a new technique to improve early recovery of continence and erectile function
Authors: A. Fuschi, Y. Al Salhi, L. Capone, A. Martoccia, P.P. Suraci, A. Asimakopoulos, S. Scalzo, F.M. Valenzi, O.A. Rera, A. Antonioni, F. Annino, A. Carbone, A.L. Pastore
Journal: European Urology (2022)
Cost of care in EGFR mutant versus wild-type non-small cell lung cancer.
Authors: Urwat Til Vusqa, Palash Asawa, Katherine Miller, Ashish Sethi, Robin Raquel Rodriguez, Andrew Friday, Gene Grant Finley
Journal: Journal of Clinical Oncology (2022)

e21084 Background: Lung cancer remains the most commonly diagnosed cancer in the United States, as well as the leading cause of cancer-related mortality. Approximately 84% of all lung cancers are non-small cell lung cancer (NSCLC). Most are diagnosed at an advanced stage when the prognosis is poorest. EGFR is the most common driver mutation in NSCLC with an incidence ranging from 20% in Caucasians, and up to 50% in Asians. Oral tyrosine kinase inhibitors (TKI) are the preferred treatment for EGFR mutant cancers as they provide better outcomes and lower toxicity than chemotherapy (Ch) or immunotherapy (ICI). Therefore, it is imperative to analyze NSCLC patients for these important driver mutations. Cancer care is expensive with the treatments and attendant costs for administration and management. We sought to compare cost of care (COC) in EGFR mutant vs wild-type NSCLC as the treatments and known toxicities differ markedly. Methods: We performed a retrospective COC analysis of NSCLC using claims data from the local BCBS affiliate Highmark (HM) members. Patients were selected based on NSCLC diagnosis codes between October 2016 and September 2018. COC was calculated from claims data to compare treatment of driver mutant NSCLC with targeted therapy versus treatment of wild-type NSCLC with ICI and/or ChT. Data used to compare COC analysis included overall medical costs defined as all medical claims incurred by a patient following start of respective therapy, oncology related medical claims, therapy costs, costs related to emergency room visits and tissue biopsies. Overall medical costs, oncology related costs and therapy costs were measured in per member per month (PMPM). We extracted cost related data at 6 months, 12 months, and 18 months into treatment. Results: Patients treated with ICI and/or ChT incurred $1000-2000 more in PMPM total medical costs than patients treated with targeted therapy. Additionally, chemoimmunotherapy patients were found to have a 5% higher emergency room admission rate along with a longer median length of stay of 1/3 day, when compared to targeted therapy patients. ICI and/or ChT patients showed a 20% higher rate of tissue biopsy and a 5-10% higher rate of repeat tissue biopsy which incurred an additional $300-$400 expense for chemoimmunotherapy patients. Conclusions: The use of targeted treatment with TKIs in EGFR mutant NSCLC patients is more cost effective than ICI and/or ChT in wild-type NSCLC. Routine screening of lung cancer patients with molecular profiling is essential, as identification of such critical driver mutations can alter the treatment plan to be more efficient, providing better care at lower cost.
Breast cancer survivors: Main physical and psychosocial problems after completion of treatment at a Brazilian cancer center.
Authors: Thiago Vidal Brito, Camilla Vieira de Reboucas, Rafaela de Brito Alves, Alayne Magalhaes Trindade D. Yamada, Adriana do Nascimento Martins, Felipe Melo Cruz
Journal: Journal of Clinical Oncology (2022)

e24057 Background: The number of breast cancer survivors has grown worldwide in recent years due to advances in treatments, however, increased survival lead to the appearance of signs and symptoms after the end of treatment that affect the quality of life of these patients in the long term. Methods: Women aged 20-60 years with a diagnosis of breast cancer and primary treatment for at least 1 year were selected. The Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire was used and sociodemographic data, life habits and clinical conditions of the participants were collected. The primary end point was to identify the main repercussions of breast cancer and its treatments. Results: A total of 87 women were enrolled for this study. The mean age was 48.5 years. The main symptoms identified were pain (15.48%), nausea (13.10%), fatigue (11.90%), hot flashes (9.52%) and insomnia (5.95%). The total FACT-B+4 score was 110.75 (SD 20.02). No statistically significant variables were identified as predictors of worsening quality of life. Conclusions: The main residual problems in breast cancer survivors 1 year after curative treatment at Hospital São Camilo Oncologia were identified, however, it was not possible to establish significant predictors of worsening quality of life. We will conduct a new interview in 1 year using others quality of life assessment instruments.
Single-nucleus RNA-sequencing analysis reveals transcriptome differences in TIGIT+ exhausted T-cell associated with poor prognosis in muscle-invasive bladder cancer (MIBC).
Authors: Shanshan Xiao, QI Wang, Liuqing Zheng, Qian Wang, Tao Wang
Journal: Journal of Clinical Oncology (2022)

e16544 Background: Compared with single-cell RNA-sequencing (scRNA-seq), Single-nuclei RNA-sequencing(snRNA-seq) can detect more genes with higher sensitivity, and it is more robust in identifying cellular markers. TIGIT+ exhausted T cells were reported significantly associated with poor prognosis in muscle invasive bladder cancer(MIBC) by flow cytometry. We aimed to evaluate unique markers of TIGIT+ exhausted T cells in MIBC via snRNA-seq and to construct a potential prognostic survival model. Methods: We collected snRNA-seq data from 25 MIBC and 4 non-MIBC patients in GSE169379, including 57 cancer tissues and 4 distant normal tissues. Meanwhile, expression profiling data and clinical information of 402 Bladder Urothelial Carcinoma(BLCA) patients were collected in The Cancer Genome Atlas (TCGA). Firstly, the snRNA-seq data was preprocessed and filtered. Next, We re-clustered T-cell subsets and abstracted TIGIT+ exhausted T cells (TIGIT+Tex), then screened out the genes uniquely expressed in TIGIT+Tex subsets by differential expression analysis. We further evaluate the correlations between uniquely expressed genes and the exhausted T cell markers, identified significantly correlated differential expressed genes, constructed a prognostic model based on multivariate cox regression analysis and exploited the patient's overall survival and disease-free survival to confirm our findings. Results: Top 10 genes (CNTN1, CTPS1, EYA1, GRIK2, FOXP2, YBX1, DACH1, SYT1, NOL4, TRIT1) of unparalleled differential up-regulation were identified from TIGIT+ exhausted T cells via snRNA-seq data. Based on the correlation analysis of TCGA expression profile data, six genes (CNTN1, CTPS1, EYA1, GRIK2, FOXP2, YBX1) that were significantly positively correlated with exhausted T cells were obtained. Next, we constructed a regression prediction model consisting of 5 genes (CNTN1, CTPS1, EYA1, GRIK2, FOXP2) through multivariate cox regression analysis based on patients’ clinical information. The model was associated with significantly poor prognosis overall survival (OS) (P &lt; 0.01,HR = 2) and disease-free survival (DFS) (P &lt; 0.01,HR = 1.6) in BLCA patients. Conclusions: In our study, Single-nuclei RNA expression profiling data revealed transcriptome differences between TIGIT+ exhausted T cells and other types of T cells. The regression model for potential prognostic survival was constructed using TCGA expression profiling data. These results demonstrated that distinctive differentially high expressed genes associated with TIGIT+ exhausted T cells may act as potential markers for predicting prognosis outcomes in bladder cancer patients.
Effect of pelvic lymph node dissection and its extent on oncological outcomes in intermediate-risk prostate cancer patients: A multicenter study of the Turkish Urooncology Association
Authors: V. Izol, F. Ok, G. Aslan, B. Akdogan, S. Sozen, E. Ozden, O. Celik, T. Muezzinoglu, L. Turkeri, N. Akdogan, S. Baltaci
Journal: European Urology (2022)